The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Edythe D London - One of the best experts on this subject based on the ideXlab platform.
-
interactions of erythro Ifenprodil threo Ifenprodil erythro iodoIfenprodil and eliprodil with subtypes of σ receptors
European Journal of Pharmacology, 1995Co-Authors: Kenji Hashimoto, Edythe D LondonAbstract:Observations of sigma (sigma) receptor heterogeneity have prompted interest in identifying ligands for sigma receptor subtypes. Selective ligands for the sigma-2 are unavailable, but [3H]Ifenprodil labels sigma-2 sites. Therefore, isomers and analogues of Ifenprodil were compared as potential sigma-2 ligands. Threo-Ifenprodil and erythro-Ifenprodil had high affinity (Ki congruent to 2 nM) for sigma-2 sites; erythro-iodoIfenprodil had moderate affinity (Ki congruent to 46 nM); eliprodil had lowest affinity (Ki congruent to 630 nM). Threo-Ifenprodil, which has less affinity for alpha 1-adrenoceptors than erythro-Ifenprodil, was slightly more selective than erythro-Ifenprodil for sigma-2 sites. These results identify threo-Ifenprodil as potentially useful for studies of sigma-2 receptors.
-
Interactions of erythro-Ifenprodil, threo-Ifenprodil, erythro-iodoIfenprodil, and eliprodil with subtypes of σ receptors
European journal of pharmacology, 1995Co-Authors: Kenji Hashimoto, Edythe D LondonAbstract:Abstract Observations of sigma (σ) receptor heterogeneity have prompted interest in identifying ligands for σ receptor subtypes. Selective ligands for the σ-2 are unavailable, but [3H]Ifenprodil labels σ-2 sites. Therefore, isomers and analogues of Ifenprodil were compared as potential σ-2 ligands. Threo-Ifenprodil and erythro-Ifenprodil had high affinity ( K i ⋍ 2 nM ) for σ-2 sites; erythro-iodoIfenprodil had moderate affinity ( K i ⋍ 46 nM ). Threo-Ifenprodil, which has less affinity for α1-adrenoceptors than erythro-Ifenprodil, was slightly more selective than erythro-Ifenprodil for σ-2 sites. These results identify threo-Ifenprodil as potentially useful for studies of σ-2 receptors.
-
Further characterization of [3H]Ifenprodil binding in rat brain☆
European journal of pharmacology, 1994Co-Authors: Kenji Hashimoto, Charles R. Mantione, Marianne R. Spada, John L. Neumeyer, Edythe D LondonAbstract:Abstract The present study was undertaken to characterize [3H]Ifenprodil binding in rat brain. [3H]Ifenprodil showed saturable, high-affinity binding at 4°C. Specific binding, defined with 10 μM Ifenprodil as a competitor, was inhibited biphasically by the s receptor ligands, GBR 12909, 1,3-di-o-tolylguanidine (DTG), and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP). At 4°C, 3 μM GBR 12909, which inhibited about 50% of specific binding of [3H]Ifenprodil, was used to mask σ receptors. Under these conditions, specific binding of [3H]Ifenprodil was inhibited potently by Ifenprodil, SL 82.0715, poly( l -arginine), poly( l -lysine), neomycin, ruthenium red, spermine, arcaine and spermidine. In the presence of 3 μM GBR 12909, Zn2+ and Mg2+ partially inhibited specific binding of [3H]Ifenprodil at 4°C. In contrast, in the absence of GBR 12909, at 37°C specific binding of [3H]Ifenprodil was partially inhibited by Zn2+, but not by Mg2+. The anatomical distribution of [3H]Ifenprodil binding at 4°C (GBR 12909 included) in rat brain closely paralleled that of [3H]MK-801 (dizocilpine) binding (r = 0.971, P
-
Further characterization of [3H]Ifenprodil binding to σ receptors in rat brain
European journal of pharmacology, 1993Co-Authors: Kenji Hashimoto, Edythe D LondonAbstract:This study was undertaken to examine further the pharmacology of [3H]Ifenprodil binding in rat brain at 37 degrees C. [3H]Ifenprodil bound specifically to membranes (Kd = 5.09 +/- 0.30 nM; Bmax = 2.36 +/- 0.19 pmol/mg protein). [3H]Ifenprodil binding was potently inhibited by sigma ligands and inhibitors of cytochrome P-450. The levorotatory enantiomers of pentazocine and SKF 10,047 were more potent inhibitors than corresponding dextrorotatory enantiomers. Furthermore, the pharmacological profile of [3H]Ifenprodil binding was highly correlated with that of sigma 2 sites, not sigma 1 sites. The results suggest that [3H]Ifenprodil labels sigma 2 sites in rat brain at 37 degrees C, and that [3H]Ifenprodil would be useful for studying sigma receptor subtypes.
Kenji Hashimoto - One of the best experts on this subject based on the ideXlab platform.
-
Potentiation of Nerve Growth Factor-Induced Neurite Outgrowth in PC12 Cells by Ifenprodil: The Role of Sigma-1 and IP3 Receptors
PloS one, 2012Co-Authors: Tamaki Ishima, Kenji HashimotoAbstract:In addition to both the α1 adrenergic receptor and N-methyl-D-aspartate (NMDA) receptor antagonists, Ifenprodil binds to the sigma receptor subtypes 1 and 2. In this study, we examined the effects of Ifenprodil on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Ifenprodil significantly potentiated NGF-induced neurite outgrowth, in a concentration-dependent manner. In contrast, the α1 adrenergic receptor antagonist, prazosin and the NMDA receptor NR2B antagonist, Ro 25-6981 did not alter NGF-induced neurite outgrowth. Potentiation of NGF-induced neurite outgrowth mediated by Ifenprodil was significantly antagonized by co-administration of the selective sigma-1 receptor antagonist, NE-100, but not the sigma-2 receptor antagonist, SM-21. Similarly, Ifenprodil enhanced NGF-induced neurite outgrowth was again significantly reduced by the inositol 1,4,5-triphosphate (IP3) receptor antagonists, xestospongin C and 2-aminoethoxydiphenyl borate (2-APB) treatment. Furthermore, BAPTA-AM, a chelator of intracellular Ca2+, blocked the effects of Ifenprodil on NGF-induced neurite outgrowth, indicating the role of intracellular Ca2+ in the neurite outgrowth. These findings suggest that activation at sigma-1 receptors and subsequent interaction with IP3 receptors may mediate the pharmacological effects of Ifenprodil on neurite outgrowth.
-
interactions of erythro Ifenprodil threo Ifenprodil erythro iodoIfenprodil and eliprodil with subtypes of σ receptors
European Journal of Pharmacology, 1995Co-Authors: Kenji Hashimoto, Edythe D LondonAbstract:Observations of sigma (sigma) receptor heterogeneity have prompted interest in identifying ligands for sigma receptor subtypes. Selective ligands for the sigma-2 are unavailable, but [3H]Ifenprodil labels sigma-2 sites. Therefore, isomers and analogues of Ifenprodil were compared as potential sigma-2 ligands. Threo-Ifenprodil and erythro-Ifenprodil had high affinity (Ki congruent to 2 nM) for sigma-2 sites; erythro-iodoIfenprodil had moderate affinity (Ki congruent to 46 nM); eliprodil had lowest affinity (Ki congruent to 630 nM). Threo-Ifenprodil, which has less affinity for alpha 1-adrenoceptors than erythro-Ifenprodil, was slightly more selective than erythro-Ifenprodil for sigma-2 sites. These results identify threo-Ifenprodil as potentially useful for studies of sigma-2 receptors.
-
Interactions of erythro-Ifenprodil, threo-Ifenprodil, erythro-iodoIfenprodil, and eliprodil with subtypes of σ receptors
European journal of pharmacology, 1995Co-Authors: Kenji Hashimoto, Edythe D LondonAbstract:Abstract Observations of sigma (σ) receptor heterogeneity have prompted interest in identifying ligands for σ receptor subtypes. Selective ligands for the σ-2 are unavailable, but [3H]Ifenprodil labels σ-2 sites. Therefore, isomers and analogues of Ifenprodil were compared as potential σ-2 ligands. Threo-Ifenprodil and erythro-Ifenprodil had high affinity ( K i ⋍ 2 nM ) for σ-2 sites; erythro-iodoIfenprodil had moderate affinity ( K i ⋍ 46 nM ). Threo-Ifenprodil, which has less affinity for α1-adrenoceptors than erythro-Ifenprodil, was slightly more selective than erythro-Ifenprodil for σ-2 sites. These results identify threo-Ifenprodil as potentially useful for studies of σ-2 receptors.
-
Further characterization of [3H]Ifenprodil binding in rat brain☆
European journal of pharmacology, 1994Co-Authors: Kenji Hashimoto, Charles R. Mantione, Marianne R. Spada, John L. Neumeyer, Edythe D LondonAbstract:Abstract The present study was undertaken to characterize [3H]Ifenprodil binding in rat brain. [3H]Ifenprodil showed saturable, high-affinity binding at 4°C. Specific binding, defined with 10 μM Ifenprodil as a competitor, was inhibited biphasically by the s receptor ligands, GBR 12909, 1,3-di-o-tolylguanidine (DTG), and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP). At 4°C, 3 μM GBR 12909, which inhibited about 50% of specific binding of [3H]Ifenprodil, was used to mask σ receptors. Under these conditions, specific binding of [3H]Ifenprodil was inhibited potently by Ifenprodil, SL 82.0715, poly( l -arginine), poly( l -lysine), neomycin, ruthenium red, spermine, arcaine and spermidine. In the presence of 3 μM GBR 12909, Zn2+ and Mg2+ partially inhibited specific binding of [3H]Ifenprodil at 4°C. In contrast, in the absence of GBR 12909, at 37°C specific binding of [3H]Ifenprodil was partially inhibited by Zn2+, but not by Mg2+. The anatomical distribution of [3H]Ifenprodil binding at 4°C (GBR 12909 included) in rat brain closely paralleled that of [3H]MK-801 (dizocilpine) binding (r = 0.971, P
-
Further characterization of [3H]Ifenprodil binding to σ receptors in rat brain
European journal of pharmacology, 1993Co-Authors: Kenji Hashimoto, Edythe D LondonAbstract:This study was undertaken to examine further the pharmacology of [3H]Ifenprodil binding in rat brain at 37 degrees C. [3H]Ifenprodil bound specifically to membranes (Kd = 5.09 +/- 0.30 nM; Bmax = 2.36 +/- 0.19 pmol/mg protein). [3H]Ifenprodil binding was potently inhibited by sigma ligands and inhibitors of cytochrome P-450. The levorotatory enantiomers of pentazocine and SKF 10,047 were more potent inhibitors than corresponding dextrorotatory enantiomers. Furthermore, the pharmacological profile of [3H]Ifenprodil binding was highly correlated with that of sigma 2 sites, not sigma 1 sites. The results suggest that [3H]Ifenprodil labels sigma 2 sites in rat brain at 37 degrees C, and that [3H]Ifenprodil would be useful for studying sigma receptor subtypes.
Bernard Scatton - One of the best experts on this subject based on the ideXlab platform.
-
Antagonist properties of the stereoisomers of Ifenprodil at NR1A/NR2A and NR1A/NR2B subtypes of the NMDA receptor expressed in Xenopus oocytes.
European journal of pharmacology, 1996Co-Authors: Patrick Avenet, Jacques Léonardon, François Besnard, David I. Graham, Jonathan Frost, Henri Depoortere, S.z. Langer, Bernard ScattonAbstract:Abstract The NMDA receptor antagonist Ifenprodil contains two asymmetric centres which give rise to four stereoisomeric forms of this molecule. The inhibitory effects of each of these stereoisomers on recombinant NMDA receptors expressed from NR1A/NR2A and NR1A/NR2B subunit combinations were studied in Xenopus oocytes by voltage-clamp recording. All four Ifenprodil stereoisomers were potent antagonists at NR1A/NR2B (IC 50 μ M), but weak antagonists at NR1A/NR2A receptors (IC 50 > 100 μ M). In heteromeric NR1A/NR2B receptors, (+) erythro - and (−) threo-Ifenprodil (IC 50 0.21 and 0.22 μ M, respectively) were about 4 times more potent than (−) erythro - and (+) threo -Ifenprodil (IC 50 0.81 and 0.76, respectively). These results show that the stereoisomers of Ifenprodil exhibit a weak though significant stereoselectivity at the NR1A/NR2B NMDA receptor subtype.
-
antagonist properties of the stereoisomers of Ifenprodil at nr1a nr2a and nr1a nr2b subtypes of the nmda receptor expressed in xenopus oocytes
European Journal of Pharmacology, 1996Co-Authors: Patrick Avenet, Jacques Léonardon, François Besnard, David I. Graham, Jonathan Frost, Henri Depoortere, S.z. Langer, Bernard ScattonAbstract:Abstract The NMDA receptor antagonist Ifenprodil contains two asymmetric centres which give rise to four stereoisomeric forms of this molecule. The inhibitory effects of each of these stereoisomers on recombinant NMDA receptors expressed from NR1A/NR2A and NR1A/NR2B subunit combinations were studied in Xenopus oocytes by voltage-clamp recording. All four Ifenprodil stereoisomers were potent antagonists at NR1A/NR2B (IC 50 μ M), but weak antagonists at NR1A/NR2A receptors (IC 50 > 100 μ M). In heteromeric NR1A/NR2B receptors, (+) erythro - and (−) threo-Ifenprodil (IC 50 0.21 and 0.22 μ M, respectively) were about 4 times more potent than (−) erythro - and (+) threo -Ifenprodil (IC 50 0.81 and 0.76, respectively). These results show that the stereoisomers of Ifenprodil exhibit a weak though significant stereoselectivity at the NR1A/NR2B NMDA receptor subtype.
-
Pharmacological characterisation and autoradiographic distribution of polyamine-sensitive [3H]Ifenprodil binding sites in the rat brain.
Neuroscience letters, 1991Co-Authors: Corinne Dana, Jesus Benavides, Hans Schoemaker, Bernard ScattonAbstract:Abstract Saturation studies with [ 3 H]Ifenprodil (in the presence of 3 μ M (+)-3-PPP and 10 μM GBR 12909) demonstrated the presence of a high-affinity ( K d = 0.45 μ M) population of binding sites in sagittal rat brain sections. This binding was inhibited by spermine (IC 50 = 69 μ M) and spermidine (IC 50 = 623 μ M) but not by putrescine (1 mM). Ifenprodil displaced this binding in a biphasic fashion with a high affinity component (IC 50 = 0.992 μ M) accounting for approximately 50% of the spermine-displaceable [ 3 H]Ifenprodil binding. The polyamine-sensitive [ 3 H]Ifenprodil binding sites were heterogenously distributed in the rat brain, the highest binding densities being found in the hippocampus and in the nucleus accumbens. The anatomical distribution of [ 3 H]Ifenprodil binding sites closely matches that previously reported for the N- methyl- d -aspartate (NMDA) receptor.
Philip M Beart - One of the best experts on this subject based on the ideXlab platform.
-
125I-Ifenprodil: Synthesis and Characterization of Binding to a Polyamine-Sensitive Site in Cerebral Cortical Membranes
Journal of neurochemistry, 1993Co-Authors: Linda D Mercer, Bevyn Jarrott, Philip M BeartAbstract:The characteristics of binding sites in rat cerebral cortical synaptic membranes labeled by 125I-Ifenprodil, a noncompetitive NMDA receptor antagonist, are described. 125I-Ifenprodil was synthesized using Na125I in the presence of chloramine-T and purified by paper chromatography. Binding of the 125I-ligand was optimal at pH 7.7 in 5 mM Tris.HCl buffer. Equilibrium binding of 125I-Ifenprodil was displaced by spermine (1 mM) but not by Ifenprodil or its analogue, SL 82.0715 (both 16.7 microM). Zn2+, Ca2+, and Mg2+ inhibited specific binding of 125I-Ifenprodil in a concentration-dependent manner, with IC50 values of 0.11, 1.1, and 1.7 mM, respectively. The dissociation constant (KD) for unlabeled Ifenprodil determined by saturation binding was 205 nM. Scatchard plots of saturation data appeared curvilinear but were best described by a single-binding-site model (Hill coefficient = 0.95), with a density of binding sites (Bmax) of 141 pmol/mg of protein. Binding of 125I-Ifenprodil was inhibited by polyamines, with a rank potency order of spermine > spermidine > putrescine = 1,3-diaminopropane. The pattern of inhibition produced by spermidine was apparently competitive. Ifenprodil congeners also fully inhibited polyamine-sensitive binding of 125I-Ifenprodil, with a rank potency order of Ifenprodil > SL 82.0715 = tibalosine > nylidrin = isoxsuprine. It was found that sigma/antitussive agents partially inhibited specific binding, but inclusion of the sigma drug GBR 12909 had little effect on the binding of 125I-Ifenprodil, suggesting this site was not involved. The binding site labeled by 125I-Ifenprodil is polyamine sensitive, has a discrete pharmacological profile, and apparently is unrelated to the sigma site.
-
Polyamine-sensitive binding of [125I]Ifenprodil in washed, frozen-thawed synaptic membranes: evidence for high affinity binding requiring an open NMDA channel.
Neuroscience letters, 1992Co-Authors: Philip M Beart, Linda D Mercer, Elizabeth L Conway, A J SearleAbstract:Abstract Binding of [ 125 I]-labelled Ifenprodil, a non-competitive N- methyl- d -aspartate (NMDA) antagonist acting at the polyamine domain, was studied in washed, frozen-thawed synaptic membranes. Under these conditions where the NMDA channel is essentially in a closed channel state and in the presence of GBR 12909, [ 125 I]Ifenprodil binding was rapid, reversible, stereospecific, saturable and to a single population of sites ( K d 76 μM, B max 140 nmol/mg protein). Binding was inhibited by spermine, spermidine and Ifenprodil congeners. These characteristics differed from those found in fresh membranes (open channel state), with Ifenprodil congeners being less potent and potencies of polyamines being unchanged. These data suggest independent, but interacting sites for polyamines and Ifenprodil congeners, the latter sensitive to endogenous modulators, labelled by [ 125 I]Ifenprodil and probably not NMDA-linked. High affinity binding of Ifenprodil congeners seems likely to require an open (‘activated’) NMDA channel.
-
[125I]Ifenprodil: a convenient radioligand for binding and autoradiographic studies of the polyamine-sensitive site of the NMDA receptor.
Neuroscience letters, 1991Co-Authors: Philip M Beart, Linda D Mercer, Bevyn JarrottAbstract:Abstract Iodination of Ifenprodil, a non-competitive NMDA antagonist, with Na 125 I Chloramin-T gave a radioligand which bound rapidly and saturably to a single population of sites (dissociation constant 145 nM) in membranes of rat cerebral cortex. In competition studies, specific binding of [ 125 I]Ifenprodil was inhibited by analogues of Ifenprodil, as well as by spermine and spermidine. Binding was sensitive to Ca 2+ , Mg 2+ and Zn 2+ . [ 125 I]Ifenprodil labelled a population of binding sites, which was topographically distributed in rat forebrain, as shown by autoradiography. [ 125 I]Ifenprodil is a useful radioligand for the investigation of the polyamine site of the N- methyl- d -aspartate (NMDA) receptor-complex.
Keith Williams - One of the best experts on this subject based on the ideXlab platform.
-
Ifenprodil, a novel NMDA receptor antagonist: site and mechanism of action.
Current drug targets, 2001Co-Authors: Keith WilliamsAbstract:Ifenprodil is a novel N-methyl-D-aspartate (NMDA) receptor antagonist that selectively inhibits receptors containing the NR2B subunit. As such, it has become widely used as a tool to study subtypes of NMDA receptors both in vitro and in vivo, and as a tool for molecular studies of the properties and regulation of NMDA receptors. Ifenprodil has an unusual form of activity-dependence and its mechanism of action may involve an increase in proton inhibition of NMDA receptors. These properties are shared by analogs or derivatives of Ifenprodil, some of which may be lead compounds for therapeutically useful NMDA antagonists. Such antagonists have potential as neuroprotectants, anticonvulsants, analgesics, and for the treatment of Parkinson's disease and other disorders of the nervous system. The location of the Ifenprodil binding site on NMDA receptors and the structural and mechanistic basis of its effects are still unknown. Recent work suggests that at least part of the Ifenprodil binding site is located in the R1/R2 domain of the NR1 subunit. This region, like the S1/S2 agonist binding domain, shares homology with bacterial periplasmic binding proteins.
-
Influence of extracellular pH on inhibition by Ifenprodil at N-methyl-d-aspartate receptors in Xenopus oocytes
Neuroscience letters, 1997Co-Authors: Albert J. Pahk, Keith WilliamsAbstract:Abstract Ifenprodil is an atypical N-methyl- d -aspartate (NMDA) receptor antagonist that selectively blocks receptors containing the NR2B subunit. It has been proposed that Ifenprodil may act at a stimulatory polyamine site on NMDA receptors, although interactions between Ifenprodil and polyamines are non-competitive. NMDA receptors are also inhibited by extracellular protons, and an interaction between protons and polyamine stimulation has been described. Using voltage-clamp recording of recombinant NR1/NR2B receptors expressed in oocytes, Ifenprodil inhibition was found to be pH sensitive with a smaller inhibition at alkaline pH. Similar effects of pH were seen on inhibition by nylidrin, eliprodil, and haloperidol, which are thought to act at the Ifenprodil binding site. The pH sensitivity of Ifenprodil block occurs at NR1B/NR2B as well as NR1A/NR2B receptors, suggesting that it is not influenced by the exon-5 insert that is present in NR1B but absent in NR1A. Protons may directly affect the Ifenprodil binding site or may alter the coupling of Ifenprodil binding to inhibition of channel gating.
-
Ifenprodil discriminates subtypes of the n methyl d aspartate receptor selectivity and mechanisms at recombinant heteromeric receptors
Molecular Pharmacology, 1993Co-Authors: Keith WilliamsAbstract:The effects of the atypical N-methyl-D-aspartate (NMDA) receptor antagonist Ifenprodil were investigated by voltage-clamp recording of Xenopus oocytes expressing heteromeric NMDA receptors from cloned NR1 and NR2 subunit RNAs. In oocytes voltage-clamped at -70 mV, Ifenprodil inhibited NMDA-induced currents at NR1A/NR2B receptors with high affinity (IC50 = 0.34 microM). The affinity of NR1A/NR2A receptors for Ifenprodil (IC50 = 146 microM) was 400-fold lower than that of NR1A/NR2B receptors. The rate of onset of inhibition by low concentrations of Ifenprodil acting at NR1A/NR2B receptors was considerably slower than the onset of inhibition seen with high concentrations of Ifenprodil acting at NR1A/NR2A receptors. The onset and recovery of blockade by Ifenprodil at NR1A/NR2B receptors were not activity dependent. The inhibitory effects of low concentrations of Ifenprodil at NR1A/NR2B receptors were not voltage dependent. In contrast, the inhibitory effects of high concentrations of Ifenprodil at NR1A/NR2A receptors were partially voltage dependent, and a greater inhibition of NMDA-induced currents was seen at hyperpolarized membrane potentials than at depolarized membrane potentials. The reversal potential of NMDA currents was not altered in the presence of Ifenprodil. Ifenprodil may act as a weak open-channel blocker of NR1A/NR2A receptors. The degree of inhibition seen with 100 microM Ifenprodil at NR1A/NR2A receptors was not altered by changes in the concentration of extracellular glycine. However, the inhibitory effect of 1 microM Ifenprodil at NR1A/NR2B receptors was reduced by increasing the concentration of glycine. Thus, part of the mechanism of action of Ifenprodil at NR1A/NR2B receptors may involve noncompetitive antagonism of the effects of glycine. These results indicate that the mechanism of action of Ifenprodil, as well as the potency of this antagonist, is different at NR1A/NR2B and NR1A/NR2A receptors expressed in Xenopus oocytes.
